Understanding how HIV-1 wreaks havoc on the CNS despite HAART remains important because people are living long enough to manifest neurologic disease. We assert there is a continuum between normal synaptic function necessary for plasticity and synaptic dysfunction during HIV-1 associated neurologic disease. Between the boundaries of plasticity and pathology, there is a reversible component of synaptic dysfunction that can be ameliorated by HAART or other adjunctive therapies. Therefore, we will investigate morphologic, electrical, and molecular events that underlie this dysfunction. HIV-1 neurotoxins affect convergent cellular pathways that increase synaptic levels of the phospholipid mediator platelet-activating factor (PAF). Although rapidly catabolized, PAF is normally involved in maintaining levels of synaptic glutamate during long term potentiation (LTP), a process that increases the efficacy of synaptic communication and is thought to be the substrate for many cognitive processes indirectly affected by HIV-1, including learning and memory. During HIV-1-induced inflammation, increased synaptic PAF is associated with excitotoxic damage to neurons. Thus we will investigate three hypotheses: (1) Prolonged exposure to PAF can alter the ability of intact synapses to achieve LTP, a measure of synaptic plasticity, by disrupting formation of dendritic spines on post-synaptic neurons either temporarily (protective "beading" response) or permanently ("synaptic apoptosis"). Here we will assess beading in affected dendrites and correlate it with synaptic responses, as well as measure caspase activation, cell viability and confirm specificity of our findings with PAF receptor antagonists. (2) Pathologic exposure to PAF will induce synaptic failure by disruption of normal mitochondrial functions leading to dysregulation of mitochondrial buffering of Ca+2 and production of ATP in stressed synapses. (3) Prolonged exposure to PAF in vivo during excitatory neurotransmission will lead to mitochondrial dysfunction and degeneration of nerve terminals, i.e. synaptic apoptosis. Thus, we will measure changes in synaptic transmission, mitochondrial function, and degeneration of nerve terminals from rodents treated in vivo with PAF. These findings will significantly advance our understanding of how HIV-1 continues to induce neurologic disease despite advances in HAART.